Charcot-Marie-Tooth disease is the most common inherited neuropathy in humans. There are no effective treatments for any form of CMT other than palliative surgery and physical rehabilitation. The neuropathy can significantly lower the quality of life in patients. We co-discovered the unprecedented large DNA duplication underlying CMT1A, an autosomal dominant subtype seen in ~60% of all CMT patients. Overproduction of the peripheral myelin protein, PMP22 underlies CMT1A while ~5% of CMT1 patients classified as having CMT1E bear a dominant point mutation in PMP22. Examination of mice over-expressing Pmp22 or bearing a Pmp22 point mutation have shown that excessive or defective Pmp22 accumulates in cytosolic or perinuclear aggregates. This is thought to decrease the amount of PMP22 protein within the Schwann cell membrane and likely contribute to the dysmyelinating phenotype. Additionally, there is evidence that point mutations in Pmp22 lower the efficiency by which the wild-type protein traffics to the cell surface. We hypothesize that a small molecule that stimulates degradation or resolution of the aggregates and possibly allows proper folding/processing of the PMP22 could have therapeutic benefit. To test this hypothesis, we have developed a high-throughput screening (HTS) assay to identify small-molecules that reduce aggregation of PMP22 bearing a point mutation. Results obtained from an initial screen of 30,000 compounds has identified 30 compounds that that reduce aggregate formation by >70%. Towards identification of a diverse set of lead compounds that can be developed as therapeutic regimens for CMT1E/1A, we propose the following Aims: (1) Examine the most active compounds after resynthesis from each of the scaffolds identified by our initial screen the effect on aggregates, their site of action, trafficking of PMP22 to the membrane and toxicity to delineate the most promising compounds. (2) Conduct medicinal chemistry driven optimization of the hit compounds and test new analogs in the primary and secondary assays and build structure-activity relationships (SAR). The goal is to identify analogs with appropriate potency, low toxicity, drug-like properties and pharmacokinetics that are suitable for in vivo evaluation in mouse models of CMT1E and CMT1A. The deliverables from Aims 1 and 2 are at least two compounds with efficacy at levels <1uM and toxicity at levels >50uM that would be ready for testing in mouse models of CMT1E and CMT1A.